tbuckley/cabot-search huggingface dataset:
Optimal dosing regimen of CD73 blockade improves tumor response to radiotherapy through iCOS downregulation
Authors: Lydia Meziani, Marine Gerbé de Thoré, Céline Clémenson, Winchygn Liu, Pierre-Antoine Laurent, Michele Mondini, Marie-Catherine Vozenin, Eric Deutsch
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Irradiation (IR) and immune checkpoint inhibitor (ICI) combination is a promising treatment modality. However, local and distance treatment failure and resistance can occur. To counteract this resistance, several studies propose CD73, an ectoenzyme, as a potential target to improve the antitumor efficiency of IR and ICI. Although CD73 targeting in combination with IR and ICI has shown attractive antitumor effects in preclinical models, the rationale for CD73 targeting based on CD73 tumor expression level deserves further investigations. Methods Here we evaluated for the first time the efficacy of two administration regimens of CD73 neutralizing antibody (one dose vs four doses) in combination with IR according to the expression level of CD73 in two subcutaneous tumor models expressing different levels of CD73. Results We showed that CD73 is weakly expressed by MC38 tumors even after IR, when compared with the TS/A model that highly expressed CD73. Treatment with four doses of anti-CD73 improved the TS/A tumor response to IR, while it was ineffective against the CD73 low-expressing MC38 tumors. Surprisingly, a single dose of anti-CD73 exerted a significant antitumor activity against MC38 tumors. On CD73 overexpression in MC38 cells, four doses of anti-CD73 were required to improve the efficacy of IR. Mechanistically, a correlation between a downregulation of iCOS expression in CD4 + T cells and an improved response to IR after anti-CD73 treatment was observed and iCOS targeting could restore an impaired benefit from anti-CD73 treatment. Conclusions These data emphasize the importance of the dosing regimen for anti-CD73 treatment to improve tumor response to IR and identify iCOS as part of the underlying molecular mechanisms. Our data suggest that the selection of appropriate dosing regimen is required to optimize the therapeutic efficacy of immunotherapy–radiotherapy combinations.
TCF3 haploinsufficiency defined by immune, clinical, gene-dosage, and murine studies
Authors: Brigette Boast, Shubham Goel, Luis I. González-Granado, Julie Niemela, Jennifer Stoddard, Emily S.J. Edwards, Sandali Seneviratne, Dominik Spensberger, Juan F. Quesada-Espinosa, Luis M. Allende, John McDonnell, Alexandria Haseley, Harry Lesmana, Magdalena A. Walkiewicz, Emad Muhammad, Julian J. Bosco, Thomas A. Fleisher, Shai Cohen, Steven M. Holland, Menno C. van Zelm, Anselm Enders, Hye Sun Kuehn, Sergio D. Rosenzweig
Journal: Journal of Allergy and Clinical Immunology (2023)

TCF3 is a transcription factor contributing to early lymphocyte differentiation. Germline monoallelic dominant negative and biallelic loss-of-function (LOF) null TCF3 mutations cause a fully penetrant severe immunodeficiency. We identified 8 individuals from 7 unrelated families with monoallelic LOF TCF3 variants presenting with immunodeficiency with incomplete clinical penetrance.
Defects in intratumoral arginine metabolism attenuate the replication and therapeutic efficacy of oncolytic myxoma virus
Authors: Parker Dryja, Heather D Curtsinger, Mee Y Bartee, Eric Bartee
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Arginine (Arg) is a semiessential amino acid whose bioavailability is required for the in vitro replication of several oncolytic viruses. In vivo, Arg bioavailability is regulated by a combination of dietary intake, protein catabolism, and limited biosynthesis through portions of the urea cycle. Interestingly, despite the importance of bioavailable Arg to support cellular proliferation, many forms of cancer are functionally auxotrophic for this amino acid due to the epigenetic silencing of argininosuccinate synthetase 1 (ASS1), an enzyme responsible for the conversion of citrulline and aspartate into the Arg precursor argininosuccinate. The impact of this silencing on oncolytic virotherapy (OV), however, has never been examined. Methods To address this gap in knowledge, we generated tumor cells lacking ASS1 and examined how loss of this enzyme impacted the in vivo replication and therapeutic efficacy of oncolytic myxoma virus (MYXV). We also generated a series of recombinant MYXV constructs expressing exogenous ASS1 to evaluate the therapeutic benefit of virally reconstituting Arg biosynthesis in ASS1 −/− tumors. Results Our results show that the in vitro replication of oncolytic MYXV is dependent on the presence of bioavailable Arg. This dependence can be overcome by the addition of the metabolic precursor citrulline, however, this rescue requires expression of ASS1. Because of this, tumors formed from functionally ASS1 −/− cells display significantly reduced MYXV replication as well as poorer therapeutic responses. Critically, both defects could be partially rescued by expressing exogenous ASS1 from recombinant oncolytic MYXVs. Conclusions These results demonstrate that intratumoral defects to Arg metabolism can serve as a novel barrier to virally induced immunotherapy and that the exogenous expression of ASS1 can improve the efficacy of OV in Arg-auxotrophic tumors.
Robust IL-2-dependent antitumor immunotherapy requires targeting the high-affinity IL-2R on tumor-specific CD8<sup>+</sup>T cells
Authors: Kathryn M LaPorte, Rosmely Hernandez, Alicia Santos Savio, Thomas R Malek
Journal: Journal for ImmunoTherapy of Cancer (2023)

Development of interleukin (IL)-2-dependent antitumor responses focus on targeting the intermediate affinity IL-2R to stimulate memory-phenotypic CD8+ T and natural killer (NK) cells while minimizing regulatory T cell (Treg) expansion. However, this approach may not effectively engage tumor-specific T effector cells. Since tumor-antigen specific T cells upregulate the high-affinity IL-2R, we tested an IL-2 biologic, mouse IL-2/CD25, with selectivity toward the high-affinity IL-2R to support antitumor responses to tumors that vary in their immunogenicity. Mice were first implanted with either CT26, MC38, B16.F10, or 4T1 and after a tumor mass developed, they were treated with high-dose (HD) mouse (m)IL-2/CD25 alone or in combination with anti-programmed cell death protein-1 (PD-1) checkpoint blockade. Tumor growth was monitored and in parallel the immune signature in the tumor microenvironment (TME) was determined by a combination of multiparameter flow cytometry, functional assays, and enumeration of tumor-reactive T cells. We show that HD mIL-2/CD25, which preferentially stimulates the high-affinity IL-2R, but not IL-2/anti-IL-2 complexes with preferential activity toward the intermediate-affinity IL-2R, supports vigorous antitumor responses to immunogenic tumors as a monotherapy that were enhanced when combined with anti-PD-1. Treatment of CT26-bearing mice with HD mIL-2/CD25 led to a high CD8+:Treg ratio in the TME, increased frequency and function of tumor-specific CD8+ T effector cells with a less exhausted phenotype, and antitumor memory responses. Targeting the high-affinity IL-2R on tumor-specific T cells with HD mIL-2/CD25 alone or with PD-1 blockade supports antitumor responses, where the resulting memory response may afford long-term protection against tumor re-emergence.
Patient-Reported Outcomes During and After Treatment for Locally Advanced Rectal Cancer in the PROSPECT Trial (Alliance N1048)
Authors: Ethan Basch, Amylou C. Dueck, Sandra A. Mitchell, Harvey Mamon, Martin Weiser, Leonard Saltz, Marc Gollub, Lauren Rogak, Brenda Ginos, Gina L. Mazza, Brian Colgrove, George Chang, Lori Minasian, Andrea Denicoff, Gita Thanarajasingam, Benjamin Musher, Thomas George, Alan Venook, Jeffrey Farma, Eileen O'Reilly, Jeffrey A. Meyerhardt, Qian Shi, Deborah Schrag
Journal: Journal of Clinical Oncology (2023)

The standard of care for locally advanced rectal cancer in North America is neoadjuvant pelvic chemoradiation with fluorouracil (5FUCRT). Neoadjuvant chemotherapy with fluorouracil and oxaliplatin (FOLFOX) is an alternative that may spare patients the morbidity of radiation. Understanding the relative patient experiences with these options is necessary to inform treatment decisions.
Tepotinib Treatment in Patients With <i>MET</i> Exon 14–Skipping Non–Small Cell Lung Cancer
Authors: Julien Mazieres, Paul K. Paik, Marina C. Garassino, Xiuning Le, Hiroshi Sakai, Remi Veillon, Egbert F. Smit, Alexis B. Cortot, Jo Raskin, Santiago Viteri, Yi-Long Wu, James C. H. Yang, Myung-Ju Ahn, Rui Ma, Jun Zhao, Aurora O’Brate, Karin Berghoff, Rolf Bruns, Gordon Otto, Andreas Johne, Enriqueta Felip, Michael Thomas
Journal: JAMA Oncology (2023)

MET inhibitors have recently demonstrated clinical activity in patients with MET exon 14 (METex14)-skipping non-small cell lung cancer (NSCLC); however, data with longer follow-up and in larger populations are needed to further optimize therapeutic approaches.
Encorafenib and Binimetinib: A New Treatment Option for <i>BRAF</i><sup>V600E</sup>-Mutant Non–Small-Cell Lung Cancer
Authors: Thomas E. Stinchcombe
Journal: Journal of Clinical Oncology (2023)

Consulting or Advisory Role: Janssen Oncology (Less than $10,000 USD in a single calendar year), Turning Point Therapeutics (Less than $10,000 USD in a single calendar year), Sanofi/Aventis (Less than $10,000 USD in a single calendar year), GlaxoSmithKline (Less than $10,000 USD in a single calendar year), Genentech/Roche (Less than $10,000 USD in a single calendar year), Daiichi Sankyo/AstraZeneca (Less than $10,000 USD in a single calendar year), Takeda (Less than $10,000 USD in a single calendar year), Eisai/H3 Biomedicine (Less than $10,000 USD in a single calendar year), G1 Therapeutics (Less than $10,000 USD in a single calendar year), Spectrum Pharmaceuticals ($10,000 USD or above in a single calendar year) Research
Association Between Duration of Immunotherapy and Overall Survival in Advanced Non–Small Cell Lung Cancer
Authors: Lova Sun, Benjamin Bleiberg, Wei-Ting Hwang, Melina E. Marmarelis, Corey J. Langer, Aditi Singh, Roger B. Cohen, Ronac Mamtani, Charu Aggarwal
Journal: JAMA Oncology (2023)

For patients with advanced non-small cell lung cancer (NSCLC) treated with frontline immunotherapy-based treatment, the optimal duration of immune checkpoint inhibitor (ICI) treatment is unknown.
Clinical Decision-Making in the Real World—The Perfect as the Enemy of the Good
Authors: Howard (Jack) West
Journal: JAMA Oncology (2023)

Lova Sun, MD, MSCE; Benjamin Bleiberg, MD; Wei-Ting Hwang, PhD; Melina E. Marmarelis, MD, MSCE; Corey J. Langer, MD; Aditi Singh, MD; Roger B. Cohen, MD; Ronac Mamtani, MD, MSCE; Charu Aggarwal, MD, MPH
Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With <i>BRAF</i><sup>V600</sup>-Mutant Metastatic Non–Small-Cell Lung Cancer
Authors: Gregory J. Riely, Egbert F. Smit, Myung-Ju Ahn, Enriqueta Felip, Suresh S. Ramalingam, Anne Tsao, Melissa Johnson, Francesco Gelsomino, Raymond Esper, Ernest Nadal, Michael Offin, Mariano Provencio, Jeffrey Clarke, Maen Hussain, Gregory A. Otterson, Ibiayi Dagogo-Jack, Jonathan W. Goldman, Daniel Morgensztern, Ann Alcasid, Tiziana Usari, Paul Wissel, Keith Wilner, Nuzhat Pathan, Svitlana Tonkovyd, Bruce E. Johnson
Journal: Journal of Clinical Oncology (2023)

The combination of encorafenib (BRAF inhibitor) plus binimetinib (MEK inhibitor) has demonstrated clinical efficacy with an acceptable safety profile in patients with
Cerebral delivery of redox-responsive lenalidomide prodrug plus methotrexate for primary central nerve system lymphoma combination therapy
Authors: Hengyu Liu, Tianqi Nie, Xiao Duan, Xinyu Zhang, Yilu Zheng, Wenhao Zhong, Haolin Chen, Congxiu Miao, Jun Wu, Dongjun Lin
Journal: Journal of Controlled Release (2023)
Overall Survival with Osimertinib in Resected <i>EGFR</i> -Mutated NSCLC
Authors: Masahiro Tsuboi, Roy S. Herbst, Thomas John, Terufumi Kato, Margarita Majem, Christian Grohé, Jie Wang, Jonathan W. Goldman, Shun Lu, Wu-Chou Su, Filippo de Marinis, Frances A. Shepherd, Ki Hyeong Lee, Nhieu Thi Le, Arunee Dechaphunkul, Dariusz Kowalski, Lynne Poole, Ana Bolanos, Yuri Rukazenkov, Yi-Long Wu
Journal: New England Journal of Medicine (2023)

Among patients with resected, epidermal growth factor receptor (EGFR)-mutated, stage IB to IIIA non-small-cell lung cancer (NSCLC), adjuvant osimertinib therapy, with or without previous adjuvant chemotherapy, resulted in significantly longer disease-free survival than placebo in the ADAURA trial. We report the results of the planned final analysis of overall survival.In this phase 3, double-blind trial, we randomly assigned eligible patients in a 1:1 ratio to receive osimertinib (80 mg once daily) or placebo until disease recurrence was observed, the trial regimen was completed (3 years), or a discontinuation criterion was met. The primary end point was investigator-assessed disease-free survival among patients with stage II to IIIA disease. Secondary end points included disease-free survival among patients with stage IB to IIIA disease, overall survival, and safety.Of 682 patients who underwent randomization, 339 received osimertinib and 343 received placebo. Among patients with stage II to IIIA disease, the 5-year overall survival was 85% in the osimertinib group and 73% in the placebo group (overall hazard ratio for death, 0.49; 95.03% confidence interval [CI], 0.33 to 0.73; P<0.001). In the overall population (patients with stage IB to IIIA disease), the 5-year overall survival was 88% in the osimertinib group and 78% in the placebo group (overall hazard ratio for death, 0.49; 95.03% CI, 0.34 to 0.70; P<0.001). One new serious adverse event, pneumonia related to coronavirus disease 2019, was reported after the previously published data-cutoff date (the event was not considered by the investigator to be related to the trial regimen, and the patient fully recovered). Adjuvant osimertinib had a safety profile consistent with that in the primary analysis.Adjuvant osimertinib provided a significant overall survival benefit among patients with completely resected, EGFR-mutated, stage IB to IIIA NSCLC. (Funded by AstraZeneca; ADAURA ClinicalTrials.gov number, NCT02511106.).
Patient resilience and distress level prior to chemotherapy based on time estimation.
Authors: Petya Kraleva, Mila Petrova, Teodor Popov, Nikolay Vladimirov Conev, Eleonora Dimitrova, Rossitza Krasteva Ruseva, Aynura Changalova, Bozhidar Iliev, Snezhina Nedeva, Tsvetan Tatarov, Georgi Zhbantov, Rosen Hadjiev, Ivan Donev
Journal: Journal of Clinical Oncology (2023)

e24184 Background: Our prospective and multicentric study aimed to determine if the effects of breast cancer patients' resilience on their distress levels are mediated by the assessment of time before initiating neo/adjuvant chemotherapy. Methods: In 104 chemo-naive breast cancer patients, time estimation was evaluated by comparing each subject's prospective estimate of how rapidly one minute passed to the actual time. The Distress Thermometer of the National Comprehensive Cancer Network was used. The range of the scale is from 0 (no distress) to 10 (extreme distress). The Connor-Davidson Resilience Questionnaire (CD-RISC), a self-reported 10-item unidimensional scale, was utilized to measure resilience. Respondents rate statements on a 5-point Likert scale ranging from 0 (not true at all) to 4 (true nearly all the time). A higher score reflects greater resilience. Based on their RISC scores, patients were divided into three groups: low (up to the 33 rd percentile), intermediate (between the 33 rd and the 66 th percentile), and high (over the 66 th percentile). Patients' time estimations were similarly divided. Cronbach's α was 0.87 for all 10 items. Results: The mean age of the patients was 53.1±12.4 years. RISC scores correlated positively with time estimation (rho = 0.31, p = 0.002) and negatively with distress levels (rho = -0.445, p &lt; 0.001). A significant negative correlation was observed between time estimation and distress levels (rho = -0.394, p &lt; 0.001). Correspondence analysis revealed a significant association across the three matching groups of RISC score and time estimation (χ 2 = 9.8, p = 0.044). The Jonckheere-Terpstra test revealed that patient estimates of time varied significantly between the three groups (p = 0.013). Using Hayes simple regression, we discovered that RISC scores were a significantly positive predictor of time estimation (b = 0.844, s.e. = 0.261, p &lt; 0.0001). Both RISC score (b = -0.136, s.e. = 0.031, p &lt; 0.0001) and time estimation (b = -0.041, s.e. = 0.011, p = 0.0005) were significant negative predictors for higher distress levels in the second regression. Conclusions: Via time estimation, patients' resilience influences distress levels prior to treatment initiation.
The impact of physician gender on patient satisfaction in an academic hematology/oncology practice.
Authors: Alaina Marie Turchi, Ahmed Bilal Khalid, Chi Mai Nguyen, Jing Su, Tarah Jean Ballinger, Shadia Ibrahim Jalal
Journal: Journal of Clinical Oncology (2023)

11022 Background: Gender disparities continue to remain under addressed in medicine. While prevalent in many forms, patient bias and perceptions toward their healthcare team can impact patient compliance and care. Health systems often gauge patient satisfaction with physicians and post these ratings online. It is possible that gender biases affect patient satisfaction scores and evaluations. Here, we assess the impact of physician gender on patient satisfaction scores and comments in an academic hematology/oncology practice. Methods: A retrospective mixed-method analysis was conducted from patient satisfaction scores and comments obtained between January and June of 2021. Patients were asked a series of three questions about their care. Patients’ response to the question, “How likely would you be to recommend this providers office to friends and family?”, was analyzed on a score of 0-10, with 10 being extremely likely and 0 being not at all likely. Patients were then asked for the primary reason for their scoring, in an open-ended format. Mixed-gender codified data was quantified from de-identified, de-gendered patient comments. To identify the differences in patient perception between male and female physicians, we specifically examined the data of positive and negative impressions of variables including professional behaviors, expertise, kindness, compassion, and interactions with ancillary staff amongst providers. Results: Patient satisfaction scores from 199 unique patients were reviewed; 140 (70.4%) were about male-identifying physicians while 59 (29.6%) were related to female-identifying physicians. The mean satisfaction score was 9.95 ± 0.29 for female physicians and 9.64 ± 1.38 for male physicians (p = 0.011). Of patients responding, 76 (38%) were male and 123 (63%) were female. Female physicians scored higher than male physicians for both male and female patients (10.0 ± 0 versus 9.65 ± 1.37 (p = 0.011) and 9.77 ± 0.60 versus 9.62 ± 1.40 (p = 0.011), respectively). Kindness and compassion were mentioned in 36% and 42% of all female physician scores, respectively, and in 29% and 33% of all male physician scores; these did not reach statistical significance (p = 0.587 and p = 0.257). 21% of all male physician scores positively mentioned physician expertise, compared to 15% of female physician scores; this also did not reach statistical significance (p = 0.434). Conclusions: Female physicians had a higher mean satisfaction score in patient evaluations than their male counterparts by both male and female patients. Numerically, more patient comments about female physicians mentioned kindness or compassion, while fewer mentioned expertise. This early work will be expanded to a larger dataset of evaluations in addition to further exploration of how female and male oncology providers are perceived by patients in multiple other categories.
Explore ALK: Alectinib activity in patients with ALK+ metastatic non-small cell lung cancer—A national real world analysis (GFPC 03-2019).
Authors: Aurélie Swalduz, Gaelle Rousseau-Bussac, Florian Guisier, Helene Doubre, Pierre Fournel, Lionel Falchero, Laurence Bigay Game, Remi Veillon, Marie Marcq, Charles Ricordel, Chantal Decroisette, Domitille Dano, Gregoire Justeau, Stéphanie Martinez, Alexis B Cortot, Hugues Morel, Laurent Greillier, Renaud Descourt
Journal: Journal of Clinical Oncology (2023)

9092 Background: Alectinib is a standard of care option in advanced ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) patients (pts), with efficacy established by phase 3 trials, in first-line and beyond. There are few efficacy data in unselected populations. Methods: The objective of this study was to evaluate the efficacy of alectinib in real-world setting. All ALK+ advanced NSCLC pts initiating alectinib, between December 13, 2017 (date of access in France) and June 27, 2020, whatever the line, were included in explore ALK study. Patient characteristics, alectinib duration of treatment (DOT), progression-free survival assessed locally (rwPFS), overall survival (OS) according to the prescription line of alectinib, the presence of brain metastases at alectinib initiation, response rate and tolerance were collected from the medical files. Results: The analysis included 223 pts: 46.2% were men, 84.7% had no smoking history or were former smokers, median age was 59 (22-101) years and 95% were adenocarcinomas. Alectinib was initiated as first-line treatment in 119 pts, with a PS of 0/1/&gt;1 in 42%/31%/27% of cases, a median number of metastatic sites of 2 (cerebral, hepatic, bone in 33%, 24% and 32% of cases). In first-line setting, after a median follow-up of 33.7 months (95%CI, 32.2-37.5), the median of rwPFS and DOT were 28.1 (95%CI, 20.7-40.4) and 26.9 (95%CI, 20.2-31.3) months, respectively. The median OS was not reach (NR), the 3-year OS rate was 72.1%. The rwPFS was not significantly different depending on whether or not the patient has brain metastases, 28.1 (95% CI, 14.5-NR) and 30.5 (85% CI, 18.9-40.4) months, respectively. The best response was complete (CR), partial (PR) and stable (SD) in 21%, 58% and 17%. The cerebral response, evaluable in 30/39 of the pts, was CR, PR and SD in 26%, 46% and 23% respectively; 33% of pts had a grade 3 adverse event, resulting in a temporary interruption of treatment in 7.6% of cases and a permanent discontinuation in 5.9% of cases. At the time of progression, 48.1% of pts had a new biopsy (66% of tissue biopsy). Efficacy data for alectinib prescribed as second line and above are summarized in the table. Conclusions: In this large real-world, cohort of unselected advanced ALK+ NSCLC pts, alectinib initiated in 1 st -line or beyond provides similar efficacy and safety results as obtained in phase III clinical trials. [Table: see text]